Poor-quality sleep and sleep insufficiency are significant risk factors for physical and mental illness and are of major public-health concern. Much effort to date has rightfully focused on the roles of subcortical populations of neurons in the regulation of biochemical and electroencephalographic responses to sleep insufficiency. Despite the body of evidence that sleep is regulated locally within functional circuits of the cerebral cortex, there is a relative paucity of experimental data on the regulation of sleep by mechanisms intrinsic to the cerebral cortex. The objective of this proposal is to determine the extent to which glycolytic metabolism within the cerebral cortex regulates electroencephalographic slow wave activity during sleep. The central hypothesis is that the temporal dynamics of slow wave activity during non-rapid eye movement sleep are regulated in a feedback relationship between slow wave activity and the glucose metabolite, lactate in the cerebral cortex. The rationale for the research proposed here is that documentation of a feedback relationship between lactate concentration and slow wave activity in the electroencephalogram will improve our understanding of the cerebral effects of sleep insufficiency and will identify the regulation of cerebral glucose utilization as a function of slep slow waves. The working hypothesis for the proposed experiments is that accumulation of lactate in the cerebral cortex during wakefulness promotes slow wave activity during subsequent sleep and slow wave activity during sleep, in turn, promotes a decline in lactate levels. We propose four specific aims designed to document this relationship. The first aim is to determine the extent to which genetic differences in the temporal dynamics of sleep slow wave activity are paralleled by genetic differences in the sleep state-dependent dynamics of lactate in the cerebral cortex. The second aim is to determine whether excessive activation of discrete functional units in the cerebral cortex, a manipulation that increases slow wave activity during subsequent sleep, also increases the rate of lactate accumulation in the cerebral cortex. The third aim is to determine whether manipulations of slow wave activity in the cerebral cortex alter lactate levels independently of sleep state. The final aim is to determine whether the processing of lactate as a glycolytic fuel by the cerebral cortex modulates sleep slow wave activity. The proposed experiments are innovative, in our opinion, because they have the potential to identify a novel regulatory relationship between sleep and cerebral glucose metabolism. The results are expected to collectively establish that sleep slow wave activity serves to release the lactate accumulated in the cerebral cortex during wakefulness. The experiments may yield novel insights into the etiology of sleep disorders and may yield novel tools for intervention in disorders of cerebral metabolism.